PROJECT SUMMARY The scientific premise of the Wake Forest Translational Alcohol Research Center (WF-TARC) is that the neurobiological substrates that contribute to alcohol use disorder (AUD) vulnerability and resilience are not fully understood. Despite the fact that alcohol misuse contributes to 88,000 deaths in America each year, the effectiveness of currently available interventions is less than desirable and is demonstrated by relapse occurring in up to 70% of treated patients. It is clear that we must better understand the neurobiology of AUD vulnerability so that patients can be identified early in the disease process and appropriate novel treatments can be developed. There is a growingly accepted three-stage model of addiction that is based on a recurring cycle of binge/intoxication, followed by withdrawal/negative affect, and ultimately preoccupation/anticipation of further use (craving). This project will focus on craving as a potential marker for AUD vulnerability as it is the primary predictor of AUD relapse. The first aim is designed to characterize the behavioral phenotypes and brain network properties associated with high craving in moderate-high alcohol drinkers (females 1-3 drinks/day, males 2-4 drinks/day). Participants must drink most days of the week but cannot have any history of, or currently meet criteria for, AUD. Ecological momentary assessment (EMA) methods utilizing iPhone technology will be used to assess craving during real time and in the participant's natural environment during normal drinking days, as well as during abstinence. Functional neuroimaging and brain network analyses will be used to examine associations between craving and brain connectivity. It is hypothesized that 1) individuals with high Alcohol Craving Experience (ACE) scores will have higher measures of EMA craving, and 2) the high ACE population will have high levels of connectivity between medial prefrontal cortex (mPFC) and posterior default-mode network (DMN) and low levels of efficiency between the mPFC and the ventral striatum and amygdala. Aims 2 and 3 will evaluate the effects of randomization to mindfulness meditation intervention versus a sham mindfulness intervention on the behavioral and brain characteristics associated with high craving in moderate-high alcohol drinkers. This will be the first placebo-controlled mindfulness meditation study to examine the behavioral and neural mechanisms supporting alcohol craving. It is hypothesized that mindfulness meditation will not only significantly reduce EMA measures of craving, but will decrease connectivity between the mPFC and posterior DMN and increase connectivity from the mPFC to the ventral striatum and amygdala. This project has the potential to guide the development of future clinical trials to better target clinical outcomes by understanding corresponding mechanisms supporting meditation-related reductions in alcohol craving. The identification of behavioral markers underlying craving as an indicator of vulnerability could lead to real-world interventions to prevent AUD.